Role of integrin alpha 8 in resolution of lung injury and repair

 简介(申请人提供)：洪智鸿博士受过肺部和重症监护医学方面的培训，对肺纤维化和ARDS的病理生理学和治疗有浓厚的临床兴趣。他的长期目标是成为一名独立的内科科学家，专注于肺间充质生物学及其在肺修复调节中的作用。为了实现这一目标，他制定了一个全面的职业发展计划，该计划建立在他之前的培训基础上。这包括一项研究计划，重点是阐明不同的肺间充质细胞群在调节肺纤维化中的作用，以及修复和学习其他肺损伤的小鼠模型。此外，洪博士还确定了一个有重点的教学培训计划，包括负责任地进行生物医学研究的培训，具有互补优势和长期合作记录的共同导师，以及一个多元化的科学和职业咨询委员会。拟议的研究将集中在整合素A8在肺修复中的作用。对整合素A8的初步研究表明，它可能在肺修复中发挥双重作用： 1)在体内的修复阶段，通过激活转化生长因子，促进纤维化；2)调节内皮修复。虽然初步数据支持整合素A8在肺修复中的作用，但尚不清楚哪个间充质群体是关键效应者。为了解决这个问题，并测试不同的间充质细胞是否利用整合素A8来调节肺修复的不同方面，洪博士将通过周细胞和常驻成纤维细胞的谱系特异性整合素A8缺失来评估肺修复，提出了三个目标。具体目标1将确定整合素A8在损伤过程中的时间和细胞分布。损伤后整合素A8表达的变化可能为其生物学活性提供重要线索。在特定的目标2中，肺肌成纤维细胞、周细胞和常驻成纤维细胞的主要前体细胞中整合素A8的缺失将解决哪些群体在纤维化中起关键作用，体外和体内研究将进一步检验其功能是否涉及转化生长因子的激活。在特定的目标3中，周细胞中整合素A8的缺失将测试周细胞是否在肺损伤后的内皮修复中利用整合素A8。

 DESCRIPTION (provided by applicant): Dr. Chi Hung is trained in pulmonary and critical care medicine and has a strong clinical interest in the pathophysiology and management of pulmonary fibrosis and ARDS. His long-term goal is to become an independent physician-scientist focused on lung mesenchymal biology and their role in regulation of lung repair. To achieve this goal, he has developed a comprehensive career development program that builds on his prior training. This includes a research program focused on elucidating the roles of different lung mesenchymal cell populations in regulating lung fibrosis and repair and learning additional mouse models of lung injury. Additionally, Dr. Hung has identified a focused didactic training program, including training in the responsible conduct of biomedical research, co-mentors with complementary strengths and a long track record of collaboration, and a diverse scientific and career advisory committee. The proposed research will focus on the role integrin a8 in lung repair. Preliminary work on integrin a8 suggests it may play a dual role in lung repair: 1) contribute to fibrosis through activation of TGFß in vivo during the repair phase and 2) modulate endothelial repair. While the preliminary data support a role for integrin a8 in lung repair, it is unclear which mesenchymal population is the key effector. To address this question and to test whether different mesenchymal populations utilize integrin a8 to mediate different aspects of lung repair, Dr. Hung will evaluate lung repair through lineage-specific integrin a8 deletion in pericytes and resident fibroblasts in three proposed aims. Specific aim 1 will define the temporal and cellular distribution of integrin a8 over the course of injury. Alterations in integrin a8 expression following injury may provide important clues about its biological activity. In specific aim 2, integrin a8 deletion in the major progenitors of lung myofibroblasts pericytes and resident fibroblasts will address which population is critical for its role in fibrosis, and invitro and in vivo studies will further examine whether its function involves TGFß activation. In specifi aim 3, integrin a8 deletion in pericytes will test whether pericytes utilize integrin a8 in endotheial repair following lung injury.